The therapeutic uses of energy for curative and preventative effects upon the human body have been known for many years. Of the various available types, electrical energy given in adequate strength and duration is the most common. The two principal effects of electrical energy upon tissues in vivo are the ionic (or chemical) effect which draws charged ions and particles towards an oppositely charged pole; and the heating (or thermal) effect which produces physiologically active amounts of heat. These principal changes in turn effect cellular activity and produce a variety of secondary physiological changes such as activity changes in the sensory vasomotor system; actions on the neuromuscular system, pH, intramembrane and salt concentration modifications; and changes in local and general metabolism. The variety of apparatus and techniques utilizing these changes now encompasses medical diathermy, hyperthermy, electrosurgery, electrical stimulation of nerves and muscles, and the use of iontophoresis for delivery of therapeutic agents. [Richard K. Kovacs, Electrotherapy and Light Therapy, Lea and Febiger, 1949; William J. Shriber, A Manual of Electrotherapy, 4th Ed., Lea and Febiger, 1978]. Of these, the therapeutic value of iontophoresis and electrical stimulation of tissues in vivo has increased enormously in recent years.
Transcutaneous electrical nerve stimulation (hereinafter "TENS") is beneficial for analgesic purposes to symptomatically relieve acute and/or chronic pain. Although the mechanism by which analgesia occurs in response to external nerve stimulation is not yet fully understood, it is well established that such analgesia does occur safely and effectively [Sjolund et al., Advanced in Pain Reserch and Therapy 3: 587-592 (1979); Serrato; J. C., Southern Medical Journal 72: 67-69 (1979)]. In TENS therapy, the afferent structures of the peripheral nervous system are the targeted sites for low voltage sinusoidal (alternating) current stimulations. Since pain is a sensory phenomenon within these afferent structures, the process of passing alternating electrical current across the skin directly influences the peripheral nervous system responses and creates an analgesic effect [Mannheimer, J. S. and Laupe, G. N., Clinical Transcutaneous Electrical Nerve Stimulation, Chapter 6, F. A. Davis Co., 1984].
Initially, electrode systems for TENS used sponges and bulk metallic wires and probes which were connected to large stationary sources of A.C. power. Such systems were of limited usefulness. In recent years, a number of commercially manufactured portable electrodes have become available to the public for TENS applications. These electrodes contain pads composed of natural or synthetic gums and gels as the materials directly in contact with the skin of the subject exemplified by the Tenzcare electrode series (3M Co.), NEURO-STIM electrodes (Consolidated Medical Equipment Inc.), Lectec karaya gum electrodes (Lectec Corp.), SUE karaya gum electrodes (Empi, Inc.), Staoderm karaya gum electrodes (Staodynamics, Inc.), and UNI-PAD natural gum electrodes (Uni-Patch, Inc.). Taken together, they form a single class of TENS electrodes with commonly shared characteristics: a construction and utility so as to be one-time use units; poor adhesion to the skin and poor cohesion qualities in the gum pads; and, a recurring tendency to irritate the skin of the user. These deficiencies have substantially reduced the effectiveness and therapeutic value of TENS electrodes.
Another, completely different, application of electrical energy is low-voltage neuromuscular stimulation to restore or improve the function of efferent motor nerve units. In these neuromuscular applications, alternating current (AC) sources are used to directly stimulate the efferent motor nerve structures in the muscle tissue and are often supplemented by direct current (DC) stimulation of denervated muscles. Neuromuscular stimulation is most beneficial in those instances in which natural muscle function is lost or diminished due to trauma; the use of electrical current offers restoration of function using artificial stimulation, directly encourages volitional effort on the part of the patient to maintain the muscle's contractility and nutritional requirements, and acts as partial blockers of noxious inputs. Although the earliest experimental work was performed by Reid in 1841 at the University of Edinborough, much controversy regarding the therapeutic effectiveness of electrical muscle stimulation followed which was resolved only about forty years ago [Fischer, An Jour. Physiol. 127: 605 (1939); Gutman et al., Lancet 1: 169 (1942); Liebesny, Arch. Phys. Ther. 23: (1942); Hines et al, Arch. Phys. Ther. 24: 69 (1943)]. Today, the recognized therapeutic values include: restoration of tone to injured muscles; prevention of intermuscular and intramuscular adhesions; the ability to keep the tendons and other parts moving so they do not become adherent to contiguous structures; and, above all, the ability to increase the blood supply to the injured tissues thereby accelerating the rate of repair by rapidly promoting absorption of waste products.
Originally, electrode apparatus for muscle stimulation consisted of only a steel or other metallic probe which was directly connected by bulk wires to a source of electrical energy. Presently available electrodes are an improvement only in that a pad formed of natural or synthetic polymers now serves as the contact surface for the skin; the various electrical circuits are attached to the polymer pad and the electrical energy is now transmitted first to the pad rather than directly to the muscular tissue. Such electrodes are exampled by the CONDUCTOL foam and karaya gum electrodes of Zimmer, Inc.
Iontophoresis, on the other hand, is a technique for the therapeutic introduction of one or more ions in solution into the tissues of the body by means of a galvanic or direct electrical current. The technique is an active delivery system for the transportation of ionized pharmacologically active ligands such as drugs through intact skin based on using the principle that ions in solution will migrate the presence of a charged electrical field. In its most common form, iontophoresis is performed by placing a transmitting electrode containing a reservoir of material saturated with an ionized drug onto the skin of the subject at the site where the drug is to be introduced. A second electrode without any ionized drug is positioned on the skin usually in opposition to the first electrode. A direct current is applied to each electrode which then becomes either positive or negatively charged in accordance with the charge of the current given. The ionized drug in the reservoir material, having been chosen to be of the same polarity as the charged first electrode itself, is driven out of the reservoir material towards the oppositely charged second electrode which acts to attract the ionized drug towards it. In this manner, the ionized drug passes out of the reservoir material and thus migrates transcutaneously through the intact skin at the desired location in its effort to each the oppositely positioned second electrode. Insofar as is presently known, only galvanic or direct electrical current has been effective for iontophoresis.
Iontophoresis, therefore, is an active method or system for transdermal delivery of pharmacologically active drugs or ligands in general. Active delivery systems are very different and distinguishable from passive drug delivery systems. Passive systems rely on natural forces and pressures such as diffusion, solubility and/or concentration density gradients for transportation and delivery of the drug or ligand into the tissues of the body; characteristically, passive systems require direct intimate contact of the drug or ligand with the skin of the subject for days or even weeks at a time and rely upon a slow, continuous, delivery of the drug in limited concentration to achieve the therapeutic effect. A detailed description of the variety of uses and inherent limitations of passive drug delivery systems and an evaluation of polymeric formulations for passive devices is provided in Water-Soluble Polymers, N. M. Bikales Editor, Plenum Press, 1973 and in Controlled Release Polymeric Formulations, D. R. Paul and F. W. Harris Editors, American Chemical Society, 1976.
Iontophoresis, on the other hand, is an actively driven system which relies on the ionization of the drug or other pharmacologically active ligand in a liquid or paste into positively and negatively charged ions and then utilizes direct (galvanic) current to propel the charged ions through the skin using a pair of oppositely charged electrodes. This phenomenon--the introduction of drugs in solution into the body--is directly due to the action of the direct current and is not caused by simple absorption of the skin from the wet pad soaked with the drug. This first was proven by the now classical animal experiments of Leduc who was the chief originator of the iontophoretic mode of medication [Leduc, S., Electric Ions And Their Use In Medicine, London Rebman Ltd., 1908] and confirmed subsequently by Puttermans et al. Arch. Phys. Med. Rehabil. 63: 176-180 (1982) and the references cited therein.
Unfortunately, subsequent research and development of iontophoretic apparatus has focused predominantly on the parameters of using galvanic current with relatively little attention, if any, to the effects and deficiencies of the material serving as the reservoir holding the ionized drug in the electrode and/or the condition of the skin or targeted tissue in the person receiving the medication [Kovacs, R., Electro Therapy And Light Therapy, 6th ed., Lea and Febiger, Philadelphia, 1949, pp. 153-165]. As a result, a series of axiomatic principles for iontophoresis have evolved and been so generally accepted as being now virtually incontestible. These axioms are: (1) Ions move at a fixed rate of speed which increases with the voltage applied to the electrode; as a corrollary, the current intensity (in millamperes) used in iontophoresis should generally be the maximum current that can be tolerated by the patient with a minimal of discomfort. (2) Ions, without regard to molecular weight, cannot and do not migrate far below the surface of the skin (epidermis and dermis) and consequently medication via iontophoresis is essentially a local or intradermal form of treatment; systemic effects, if any, are an exception and are not to be expected. (3 ) The time necessary for ionized drug transfer will vary with the characteristics and the potency of the specific drug; a therapeutic treatment period, regardless of electrode construction will vary nominally from five minutes to several hours or even days in duration. (4) The reservoir material in the electrode containing the ionized drug in solution should be an absorbent material of substantial thickness or take the form of a medicated water bath; the concentration of all drugs in solutions retained and held by the reservoir material within the electrode should be one percent or less as no advantage is gained by increasing the concentration of the drug in solution above this 1% level. [Kovacs, R., Electrotherapy And Light Therapy, 6th ed., Lea and Febiger, Philadelphia, 1949; Kahn, J., Low Voltage Technique, 3rd ed., New York, 1978; Shriber, W. J., A Manual Of Electrotherapy, 4th ed., Lea and Febiger, Philadelphia, 1978].
Because of these dogmatic axioms, nearly all of the recent advances in this art have been directed to one of two areas: specific therapeutic applications for iontophoresis whereby systemic toxicity can be virtually eliminated by using minute amounts of drug in high concentration delivered at a localized site; and specific improvements in the electrical circuitry of the energy source or electrode assembly as exemplified by the improved electrical controls and safety circuits which enhance the safety and comfort aspects for the subject. Each of these areas represent divergent directions of research which, although individually useful, accept and rely upon the general axioms previously stated. Exemplifying the development of specific therapeutic applications for iontophoresis are the following: administering pilocarpine in a diagnostic test for cystic fibrosis in infants and children [Gangarosa, L. P., Meth. And Find. Exp. Clin. Pharmacol., 2: 105-109 (1979)]; local anaesthesia of the eardrum [Comeau et al., Arch. Otolaryngyl. 98: 114 (1973)]; iontophoretic delivery of idoxuridine for recurrent herpes labialis [Gangarosa et al., Meth. And Find. Exptl. Clin. Pharmacol. 1: 105-109 (1979)]; anaesthesia of the tympanic membrane [Brummett et al., Trans. Am. Acad. Aphthalmol. Otolaryngol. 78: 453 (1974)]; delivery of dexamethasone for reduction of inflammation [Glass et al., Int. Soc. Trop. Dermat., 19: 519-524 (1980)]; anaesthesia for tooth extraction [Gangarosa et al., Meth. Find. Exp. Clin. Pharm. 3: 83-94 (1981)]; and delivery of heavy metals (e.g., copper and zinc) and of vasodilating drugs (histamine, mechoylyl, cocaine, epinephrine, and aconitine) [Shriber, W. J., A Manual Of Electrotherapy, 4th ed. Lea and Febiger, Philadelphia, 1978].
In direct contrast, efforts to improve the electrical circuitry of the power source or the electrode assembly are illustrated by the following: use of a light-coupled pulse generator and current monitor [Waud, D. R., J. Appl. Physiol. 23: 128-130 (1967)]; a completely self-contained electrode [U.S. Pat. No. 3,677,268]; an iontophoretic device with reversible polarity [U.S. Pat. No. 4,406,658]; an electrophoretic device whose current is periodically interrupted by relatively short pulse of current in the opposite direction [U.S. Pat. No. 4,340,047]; a self-contained iontophoretic apparatus with a pair of electrodes in close proximity to one another [U.S. Pat. No. 4,325,367]; a method of applying electricity to a selected area to minimize buring of the skin [U.S. Pat. No. 4,211,222]; a burn protection electrode structure [U.S. Pat. No. 4,164,226]; specific circuitry for application of fluoride in teeth [U.S. Pat. No. 4,149,533]; and a current adjustment circuit for iontophoretic electrodes [U.S. Pat. No. 3,991,755].
It is apparent that there has been very little interest in or attention to that singular component of the iontophoretic electrode which retains and holds the active ionized drug to be delivered--the material forming the reservoir. For many years, the now classical method for iontophoresis required only a reservoir material which was absorbent and of sufficient thickness to accept a stainless steel probe. Materials considered suitable for use as a reservoir included paper (often in the form of paper towels); household towels made of cotton, cellucotton or felt; and even asbestos fabric. Traditionally, the chosen reservoir material was soaked in warm water, covered with a block of tin foil cut to meet the dimensions of the reservoir and held in position using a sandbag or rubber bandage.
This melange, comprising the electrode proper, was then placed over the target area. The skin in this area was previously massaged with the ionized ligand in ointment form, or washed with a towel previously soaked in the medicated solution if it was dispersed in a fluid. Galvanic current was conveyed to the reservoir material using alligator chips attached to the tin foil backing and/or by lead wires attached to the current source. [Shriber, W. J., A Manual of Electrotherapy, 4th ed., Lea and Febiger, Philadelphia, 1978; Kovacs, R., Electrotherapy And Light Therapy, 6th ed., Lea and Febiger, Philadelphia, 1949, p. 156].
Only recently has there been any departure from the classical approach with regard to the materials which may be suitable for use as the reservoir in an iontophoretic electrode. For example, Jacobsen et al., demonstrated that some gels comprising as karaya gum and other polysaccharides are nominally useful as reservoir materials if the thickness-to-width ratio is restricted to about 1:10 [U.S. Pat. No. 4,416,274]. A secondary development by Jacobsen et al., was an electrode having a discrete chamber or enclosure for the dispersion of a drug within a liquid carrier prior to driving the ions through a microporous membrane for migration into the subject [U.S. Pat. No. 4,419,092]; this particular device has been commercialized by Motion Control, Inc. and commercial embodiments are now available to the public. The use of agar-agar gels in a cup-like receptacle for ionized drug delivery has also been described [U.S. Pat. No. 4,383,529]; unfortunately, agar-agar has been found to degrade upon addition of galvanic current and thus delivers degradation byproducts such as proteins and iodine to the targeted site concomitantly with delivery of the drug. Often these byproducts are unwanted or are undesirable in the subject.
Overall therefore, while advances have occurred enlarging the therapeutic uses of energy, it is apparent that there has been little consistency in approach, no analysis of common problems, and no overlap of structural design efforts for improving electrode apparatus and assemblies. To the contrary, each type of electrode (be it for transcutaneous nerve stimulation, or for neuromuscular stimulation, or for iontophoresis) has been altered and designed independently with almost a complete disregard of the advanced in other types of electrodes. Although there now appear to be some commonly shared features among them (particularly in commercially available embodiments), there has been no recognition and no awareness to date that the choice and characteristics of the material to be used as the pad or reservoir is the major, if not decisive, factor in determining the compatibility and effectiveness of electrodes generally without regard to application.